The disclosures of all publications, patents, patent application publications and books referred to in this application are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
In a significant number of patients suffering from atherosclerotic coronary artery disease, introduction of a catheter into the affected vessel, inflation of a balloon to relieve the obstruction (angioplasty), and implantation of a stent to maintain lumen permeability are performed as part of their treatment. Stents are small metal tubes or scaffolds that can be inserted via a balloon catheter into the narrowed segment of the artery. When the balloon is inflated, the stent expands and is embedded into the artery vessel wall, which thus opens the previously narrowed segment of artery. The balloon is then deflated and removed along with the catheter, and the stent is left behind to serve as a metal framework for the artery (FIG. 2). Although stented arteries have less chance of renarrowing (restenosis) than arteries opened with a balloon alone, in-stent restenosis can still occur in more than 1 in 5 patients after stent placement (FIG. 3). Because restenosis within the stented region of a heart artery is caused by tissue growth—mainly driven by proliferation, migration and matrix synthesis of vascular SMCs—some stents, called drug-eluting stents (DESs), are coated with medication that can be slowly released into the arterial wall to inhibit or prevent this tissue growth. DESs markedly reduce the rate of restenosis and the need of revascularization. In fact, about 1 in 10 patients develops restenosis in the first several years after drug-eluting stent implantation, a rate about half of that seen for stents without medication. However, current DESs have significant limitations. These DESs are designed to release pharmacological agents into the vessel wall in order to inhibit the response to injury causing restenosis; unfortunately, the action of agents currently in use is not confined to inhibition of SMCs, but extends to other cell types, including ECs. All the medications released by existing DESs decrease EC migration and proliferation; moreover, they induce EC expression of tissue factor, an important pro-coagulant glycoprotein. Existing DESs also decrease proliferation, differentiation, and homing of endothelial progenitor cells, which are believed to contribute to re-endothelialization after stent implantation. These inhibitory effects on EC biology result in delayed endothelialization (EC coverage) of stent struts, which leaves exposed stent components that trigger thrombosis and inflammation and may result in in-stent thrombosis and consequent myocardial infarction and death. In order to reduce the risk of in-stent thrombosis, patients treated with existing DES must receive a long-term dual antiplatelet therapy, usually a combination of aspirin and clopidogrel for at least 1 year, which increases the risk of bleeding and health care costs. Existing DES cannot be used in patients in whom this prolonged antiplatelet therapy is contraindicated.
The present invention addresses the need for improved stents which encourage endothelialization and inhibit restenosis.